Background

Cluster headaches are also known as Horton’s syndrome. TACs (Trigeminal autonomic cephalgia), the major kind of headache, are most frequently manifested as cluster headaches. As just 0.1 percent of the population suffers from them, it is at best challenging to investigate the disease process. Considering their rarity, they should always be recognized and treated because they have established a reputation as being one of, but not the most serious forms of headaches. 

Given that FDR (first-degree relatives) had an 18-fold increased risk of being diagnosed with Horton’s syndrome, there is some evidence of genetic correlation. Uncertainty surrounds the inheritance mode, though. While a few families appear to transmit the symptoms down in an autosomal dominant pattern, others appear to do so. 

A single headache with at minimum one ipsilateral autonomic sign qualifies as a cluster headache. Up to 8 times per day, such headaches can happen every other day. They typically happen around the same hour of the day, most frequently during the night. Most patients experience repeated attacks for days to months at a time, accompanied by remissions lasting months or even years. 

Epidemiology

0.1 percent of the population in general experiences cluster headaches. Though it can begin at any age, the average age of onset is around 30. Although a recent study has revealed that the proportion has been declining with time, men are 3 times as likely as women to experience this illness. 

This occurrence may be attributable to increased diagnostic performance; frequently, Horton’s syndrome is misdiagnosed in women as migraines. It’s interesting to note that tobacco users make up 85% of all cluster headache sufferers. 

If a patient has a first-degree family who has been diagnosed with cluster headaches, their chances of getting one are increased by eighteen times. According to a wide range of research, between thirty and eighty percent of those who suffer from Horton’s syndrome have already sleep apnea. 

Anatomy

Pathophysiology

Horton’s syndrome can have several different causes, as was already mentioned. There seems to be a diurnal regularity, which prompts research into the hypothalamus and, ultimately, morphological studies that reveal anomalies. The trigeminovascular network and parasympathetic nerve fibers are also involved. 

Some studies have hypothesized that instability of the autonomic nervous system and a deficiency in the central route of pain control cause problems in the supraspinal control of cognitive processing and pain. Investigators also have discovered abnormalities in the GABA, ion channel, as well as inflammation-related molecular signaling pathways, particularly histamine, cell surface proteins, and Interleukin-2. 

Given that pituitary adenylate cyclase-activating polypeptide (PCAP), rises in the blood throughout attacks, genetic testing has identified a number of potential sources, such as Period circadian protein homolog 3 protein (related to the circadian clock), orexin-B (related to the sleep-wake routine, modulation of nociceptive neurotransmission, and food consumption), and pituitary adenylate cyclase-activating Polypeptide receptor allele. All proposed genetic routes require further investigation. 

Etiology

Horton’s syndrome has an unclear cause. Numerous hypotheses have been put out and investigated. Sadly, sample sizes are constrained because people with this illness are rather uncommon. The parasympathetic nervous system responsible for the trigeminal-autonomic reflex pathway, the hypothalamus region, and the trigeminovascular system, are all known to be connected. 

It is unclear how these components interact to produce severe headaches, though. The genetics of the illness has also been extensively studied, leading to a biochemical evaluation, because there is a clear genetic connection. A painful attack and vasodilation are inextricably linked. Perivascular sensory neurons generate widening of blood vessels (vasodilation) when the trigeminovascular system is activated. 

The trigeminal nerve terminal is thought to be unilaterally activated; however functional MRI hasn’t shown this to be the case. Additionally, the number or duration of attacks is unaffected by a complete trigeminal nerve root division. This lack of improvement only demonstrates that there are other components to the cluster headache; it does not exclude the trigeminovascular system as a contributing factor. 

Horton’s syndromes are definitely linked to the hypothalamic. Attacks occur most frequently at night and provide a circadian regularity. When the patient is experiencing an attack, PET (positron emission tomography) scans have revealed activity of the inferior hypothalamus grey volume. Studies on morphology have revealed anatomic irregularities in the same hypothalamic area. 

However, it should be noted that activation of the hypothalamic does not cause attacks. Also, some studies point to the possibility that stimulating the hypothalamus could stop an attack. 

The parasympathetic nerve fibers, which are a component of the trigeminal autonomic response, are what trigger the autonomic signs, such as rhinorrhea, lacrimation, and facial vasodilation. Similar to the hypothalamic, it is a well-known contributor to cluster headaches, however, it is unclear what causes the trigeminal reflex to activate. 

Risk elements: 

• Gender male 
• Older than 30 years old 
• Alcohol consumption 
• Previous brain injury or surgery 

Genetics

Prognostic Factors

It was estimated that 25% of the cases of cluster headaches rarely reoccur in the patient’s lifetime. Another 10 to 20% of patients will develop treatment resistant cluster headaches and another 15 to 20% may have recurrent cluster headaches. This sickness tends to cure and could take 15 years or less at most. It is a well-known fact that patients can experience various undesirable outcomes and consequences affecting their mental state. Physical suffering and a deterioration of the quality of life are inevitable. 

Clinical History

Age Group: Cluster headache is more common in adults and the onset of the disease most commonly falls within the age range of between 20 to 40 years. 

Physical Examination

Ipsilateral Autonomic Features: 

Lacrimation: It is common to wake up with one eye that has a little discharge and looks red or teary. 

Conjunctival Injection: It also affects the conjunctiva. 

Rhinorrhea or Congestion: The nasal passages might become congested or become runny. 

Anterior lesions: There may be swelling of the eyelid on the side of the face affected. 

Forehead and Facial Sweating: This is because the forehead and face on the affected side may be sweating. 

Miosis and/or Ptosis: They may include constriction of the pupil in the affected side (miosis) and drooping of the eyelid (ptosis). 

Age group

Associated comorbidity

Comorbidities: Cluster headache is known to coexists with several conditions and they include: 

Psychiatric comorbidities: Cluster headache is increasingly associated with anxiety and depression. 

Other comorbidities: Other comorbidities have been known to include hypertension, back pains, and sleep disorders as well. 

Associated activity

Acuity of presentation

Acuity: A cluster headache is characterized by a severe, sudden onset of pain and is usually described as being like a stabbing or burning pain, on one side of the head. It can be severe and chronic, and incidence of symptoms such as loss of consciousness or other neurological abnormalities is common. 

Differential Diagnoses

• Paroxysmal Hemicrania: This is a headache, confined to one side of the head, typically lasting 2 to 30 minutes and has a good response to indomethacin. 
• Short-Lasting Unilateral Neuralgiform Headaches with Conjunctival Injection and Tearing (SUNCT Syndrome): This is a very rare disorder and hence presents with one-sided headaches that take between 5 and 240 seconds to peak, occurring 3 to 200 times per day and cannot be easily treated. 
• Short-Lasting Unilateral Neuralgiform Headaches with Cranial Autonomic Symptoms (SUNA): This condition is marked by short, severe headaches with autonomic features, resembling those of the cluster headache. 
• Hemicrania Continua: This condition involves chronic unilateral headache which has good response to indomethacin. 
• Probable Trigeminal Autonomic Cephalgia: This condition is a chronic headache disorder which presents with most but not all features of cluster headache. 
• Tension Headache: This condition is defined by bilateral headaches determined as a throbbing ache or a pressing ache which is linked with fatigue, pericranial muscle tenderness, or sleep problems. 
• Trigeminal Neuralgia: This condition is described as paroxysmal, electrical, sharp or stabbing pains occurring in the distribution of the trigeminal nerve and lasting only a few seconds and is considered as being largely intractable. 
• Primary Stabbing Headache: This condition is characterized by brief, stabbing pain without cranial autonomic symptoms 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Abortive Therapy 

Oxygen Therapy: Oxygen at a concentration of 100 percent terminates cluster headache attacks. Even within 15 minutes it can relieve the symptoms of headache.” 

Triptans: Triptans are also effective abortive treatments for cluster headache, which is a severe type of migraine. It leads to vasoconstriction and has anti-inflammatory properties which are useful in managing the condition. There are two types of formulations: subcutaneous and intranasal. 

Ergot Derivatives: Results of cluster-bursting research confirm that ergot alkaloids are capable to cope with the main problem – the acute cluster headache pain. They induce constriction of cerebral vessels which leads to decrease in blood perfusion in the head area. 

Transitional Therapy 

Steroids: Steroids can also be prescribed when a patient is experiencing the cluster period with the aim of reducing the number of attacks in the long run. 

Greater Occipital Nerve Blocks: These blocks can help to decrease the rate and intensity of the cluster attacks, but cannot be taken on a regular basis because of the side effects. 

Preventive Therapy 

Suboccipital Blockade: This is a perfect preventive measure embarked on by injecting local anesthetic solution in the suboccipital space. 

Verapamil: Verapamil is the most common agent used to prophylactically prevent cluster headache. It prevents the influx of calcium ions in vascular smooth muscles which results in vasodilation. 

Lithium: For cluster headache prophylaxis, lithium is considered as a first-line treatment, but the exact pathway is still not well understood. 

Anticonvulsants: This could help prevent cluster headaches because drugs like topiramate are used to operate central sensitization. 

Corticosteroids: High-dose corticosteroids are useful for acute flareups of cluster headache, with pain relief occurring within 8-12 hours. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-a-non-pharmacological-approach-for-treating-cluster-headache

Oxygen Therapy: Nasal oxygen therapy includes breathing pure oxygen through a mask, which can offer effective assistance during cluster headache attack. This is typically one of the best treatments which can be offered except using drugs. 

Lifestyle and Behavioral Modifications 

Regular Sleep Schedule: Sticking to a regular sleep schedule is another effective way of avoiding attacks. 

Hydration: Maintaining good personal hygiene is crucial since conditions such as dehydration cause headaches. 

Avoiding triggers: Some of the factors that may be avoided include alcohol, smoking, and strong smells to minimize incidences of headaches. 

Stress Management Techniques 

Relaxation Techniques: Stress management techniques like deep breathing, meditation, and progressive muscle relaxation may help prevent headaches. 

Biofeedback: This technique is aimed at regulating functions like heart rate, blood pressure and muscle tension to lessen the headache. 

Physical Therapies 

Acupuncture: Certain people who suffer from cluster headache have discovered that they can get relief through acupuncture. 

Chiropractic Care: Adjusting manually may assist in easing out headache signs in some individuals. 

Dietary Changes 

Elimination Diet: Moreover, it is helpful to try to recognize products that may lead to development of headache and exclude them from the diet. 

Magnesium and Melatonin: There are many supplements for heart attacks, such as magnesium and melatonin, that we can take in order to reduce risks for some people. 

Cognitive Behavioral Therapy (CBT) 

CBT can assist to control psychological treatments of chronic pain and may also lower the occurrence frequency of headache attacks by dealing with tension and other psychological basis. 

Role of Neurologics

Zolmitriptan (Zomig, Zomig-ZMT, Zomig Nasal Spray): It is a selective agonist of 5-hydroxytryptamine-1 (5-HT1) receptors in the cranial arteries that results to vasoconstriction and limited inflammation produced by antidromic neuronal transmission of CHs. It can also reduce intensity of the headache within 15 minutes after injecting it subcutaneously. The recently introduced intranasal formulation is an excellent option compared to the mandatory self-injection. 

Naratriptan (Amerge): It is a selective 5-HT1 receptors agonist in cranial arteries and its action includes also vasoconstrictor and anti-inflammatory effect associated with antidromic neuronal activation in CH. It may also alleviate headache intensity in as soon as 15 minutes following subcutaneous injection of the drug. 

Sumatriptan succinate (Imitrex, Alsuma, Sumavel DosePro): It is the selective agonist of 5-HT1 receptors of the cranial arteries and helps to relieve inflammation of arteries and capillaries due to antidromic neuronal transmission in CH. It reduces headache severity in patients within 15 minutes once administered as a subcutaneous injection. The intranasal form, which is available in the United States, is a more convenient method of administering the drug than self- injection. 

Rizatriptan (Maxalt, Maxalt-MLT): A selective 5-HT1 receptor agonist, Rizatriptan reduces inflammation in the cranial arteries which are typically involved during migraine headaches. 

Almotriptan (Axert): It is indicated for the management of acute migraine and is formulated as selective 5-HT1B/1D receptor agonist. It causes vasoconstriction of cranial blood vessels, suppresses the release of neuropeptides, and attenuates pain sensation in the trigeminal nervous system. 

Role of CGRP Monoclonal Antibodies

Galcanezumab (Emgality): It is a monoclonal antibody and the first medication approved by the FDA for the prevention of episodic cluster headache in adults. It is a monoclonal antibody that selectively inhibits the activity of calcitonin gene-related peptide (CGRP), a biomolecule that plays a central role in the development of headache. 

Role of Ergot Derivatives

Ergotamine (Ergomar): Ergotamine is a potent direct vasoconstrictor which leads to vasoconstriction of peripheral blood vessels and also of cranial circulation. In its many formulations, it may be taken orally, inhaled, administered rectally or in the form of a sublingual dose. Oral administration is not as effective as other forms of administering the medication for acute cluster attacks. 

Dihydroergotamine (D. H. E. 45 injection, Migranal): Another ergot derivative is the dihydroergotamine that has alpha adrenergic antagonist and serotonin antagonist property as well. It is obtainable in IV or intranasal forms and it differs from ergotamine tartrate in terms of arterial vasoconstriction. 

Role of Topical analgesics in the treatment of cluster headache

Capsaicin: It is derived from the chili peppers which induces the release of substance P is a key pain mediator. Substance P can be gradually depleted with repeated treatments, preventing reaccumulation and offering long-term pain relief. It has been used in clinical studies to treat cluster headaches. 

Role of Calcium Channel Blockers

Verapamil: It is one of the most useful calcium channel blockers for prophylaxis of CH: This drug prevents calcium ions from entering slow channels, select voltage-sensitive areas or vascular smooth muscle, resulting in vasodilation. It can be taken in conjunction with ergotamine or lithium. 

use-of-intervention-with-a-procedure-in-treating-cluster-headache

Greater Occipital Nerve Block: It consists of administering a local anesthetic through an injection to the greater occipital nerve, which begins at the back base of the skull and extends to the back of the head. This procedure together can help in managing pain and in the reduction of the incidences of attack of cluster headache. 

Suboccipital Block: It includes use of a local anaesthetic agent that is injected in the suboccipital area on the lower part of the skull. This procedure can also be useful in decreasing the severity of the pain and the rate of occurrence of cluster headache. 

Sphenopalatine Ganglion Block: It involves the administration of a local anaesthesia through a route at the sphenopalatine ganglion which is situated in the nasal passage. This procedure can alleviate the pain and prevent the recurrence of the cluster headache attack. 

use-of-phases-in-managing-cluster-headache

Abortive therapy is aimed at easing or halting acute cluster headache attacks when they begin. These include oxygen therapy drugs, triptans, and ergot derivatives. Adjuvant therapy can be used as transitional therapy which can give short-term therapy while the preventive therapy establishes itself. Although steroids are effective in treatment, they cannot prevent the development of a cluster period. Greater occipital nerve blocks are effective in decreasing the frequency and severity of cluster attacks but can cause adverse effects and therefore cannot be administered in the long term. Cluster therapy is intended to decrease the rate of individual cluster headache attacks and lessens the severity of each attack. Some of these include verapamil, lithium, topiramate, among others, and the CGRP monoclonal antibody antagonists include Galcanezumab. 

Medication

Future Trends

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References

Cluster Headache:ncbi.nlm.nih